Several fines of investigation suggest that the integrity of the prefrontal cortex may be particularly salient for understanding the pathophysiology of bipolar affective disorder. Specifically, the frontal system has been shown to play a major role in the assimilation and integration of information and in the ability to plan, inhibit, and initiate emotional and behavioral responses. The application of a combined functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) protocol provides an important approach for measuring functional and structural changes associated with frontal dysfunction. Whereas investigations to date have focused on measures of brain volume or function to characterize brain changes in bipolar patients, we now propose the assessment of cortical activation in response to cognitive and emotional challenge paradigms in addition to assessments of white matter microstructure as a means of measuring network changes. Anatomic studies of patients with bipolar disorder have reported alterations of prefrontal and limbic regions, while functional neuroimaging studies indicate anomalous response of neural circuits both within and between these cortical regions. [unreadable] [unreadable] In preliminary BOLD fMRI studies, we found that bipolar patients as compared with normal control subjects produced altered activation of the prefrontal cortex and amygdala during the completion of a facial affect task and altered prefrontal activation during the completion of the interference subtest of the Stroop test. These findings complement previous reports of cognitive deficits in bipolar patients on tests that are sensitive to frontal functions and suggest that this region may play a crucial role in the pathophysiology of bipolar disorder. The proposed research builds on existing neurobiologic models of affective disorders and extends our preliminary findings by applying fMRI and DTI techniques to the evaluation of 40 first episode bipolar patients, 40 healthy control subjects, and 24 chronic bipolar patients while performing cognitive and affective challenge measures. First episode patients will be evaluated in a longitudinal fashion, completing all study measures at baseline (treatment-naive) and 12 months following study enrollment. Structural equation modeling will be used to measure a model of limbic circuitry dysfunction in patients with bipolar disorder. Measures of DTI will be correlated with path coefficients in an attempt to clarify changes in connectivity between study groups. Data generated from this project will provide new insights into the functional connectivity underlying bipolar disorder and may lead to improved intervention and treatment. [unreadable] [unreadable]